Immune mechanisms affected by cyclooxygenase inhibition combined with antiviral treatment in calves infected with bovine respiratory syncytial virus

Authors: LEBEDEV, MAXIM - University Of California, Davis; WALSH, PAUL - Sutter Medical Center; Newman, John; MUTUA, VICTORIA - University Of California, Davis; MCELIGOT, HEATHER - University Of California, Davis; CARVALLO CHAIGNEAU, FRANCISCO - Virginia Tech; GERSHWIN, LAUREL - University Of California, Davis

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/10/2025
Publication Date: N/A
Citation: N/A

Interpretive Summary: Bovine respiratory syncytial virus (BRSV) infection is one of the most significant problems in both the dairy and beef production sector, inflicting severe economic damage to the industry. The respiratory difficulties with this viral infection are associated with a change in the type of antibodies produced by immune cell along with the production of proinflammatory lipid mediators. We show that combining the anti-inflammatory drug ibuprofen with an anti-viral fusion protein inhibitor improved treatment over ibuprofen alone, and prevented the increased viral loads observed with ibuprofen. These findings support a novel therapy for this disease when identified early.

Technical Abstract: Bovine respiratory syncytial virus (BRSV) infection is a part of the bovine respiratory disease complex. This is one of the most significant problems in both the dairy and beef production sector, inflicting severe economic damage to the industry. BRSV manifests clinically as a respiratory syndrome, affecting both upper and lower respiratory tract, including bronchiolitis with dyspnea and wheezing. It has been shown previously that these symptoms caused by IL-4/IL-13 domination in the immune response are associated with an antibody isotype switch to IgE. Prostaglandin production, such as PGE2 is another factor contributing to the pathogenesis of the disease. In this work we demonstrated the effects of ibuprofen and antiviral fusion protein inhibitor (FPI) separately and combined. We showed the synergistic effect of ibuprofen in combination with FPI on antiviral effects and suppression of PGE2, resulting in improved cytoplasmic toll-like receptor recognition and humoral immune responses mediated by antimicrobial peptide in lungs. We also demonstrated a Th1/Th2 balance shift towards a Th2 response in lungs and mediastinal lymph nodes, favorable to IL-4/IL-13 responses. This shift may explain the factors of higher viral loads and lack of the clinical response to ibuprofen administered without FPI. Additionally, we demonstrated that endocannabinoids may play a crucial role as natural regulators of the inflammation, adaptive immune response, and resolution of the inflammatory process.